title: Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart.
abstract: Both preclinical and clinical studies suggest that brief cycles of ischemia and reperfusion in the arm or leg may protect the heart against injury following prolonged coronary artery occlusion and reperfusion, a phenomenon known as remote ischemic preconditioning. Recent studies in mice indicate that increased plasma interleukin-10 (IL-10) levels play an important role in remote ischemic preconditioning induced by clamping the femoral artery for 5 min followed by 5 min of reperfusion for a total of three cycles. In this study, we demonstrate that remote ischemic preconditioning increases plasma IL-10 levels and decreases myocardial infarct size in wild-type mice but not in littermates that are heterozygous for a knockout allele at the locus encoding hypoxia-inducible factor (HIF) 1α. Injection of a recombinant adenovirus encoding a constitutively active form of HIF-1α into mouse hind limb muscle was sufficient to increase plasma IL-10 levels and decrease myocardial infarct size. Exposure of C2C12 mouse myocytes to cyclic hypoxia and reoxygenation rapidly increased levels of IL-10 mRNA, which was blocked by administration of the HIF-1 inhibitor acriflavine or by expression of short hairpin RNA targeting HIF-1α or HIF-1β. Chromatin immunoprecipitation assays demonstrated that binding of HIF-1 to the Il10 gene was induced when myocytes were subjected to cyclic hypoxia and reoxygenation. Taken together, these data indicate that HIF-1 activates Il10 gene transcription and is required for remote ischemic preconditioning.
authors.affiliation: Departments of Medicine, Biological Chemistry, Pediatrics, Oncology, and Radiation Oncology, Institute for Cell Engineering, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Zheqing
authors.initials: Z
authors.lastname: Cai
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.forename: Huiwang
authors.initials: H
authors.lastname: Zhan
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000167:Acriflavine / Q000494:pharmacology; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016753:Interleukin-10; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D000167:Acriflavine; D051057:Proto-Oncogene Proteins c-akt
keywords: cardiac surgery; cardioprotection; coronary heart disease; myocardial infarction